Research (2015) 38, 856–861 & 2015 The Japanese Society of Hypertension All rights reserved 0916-9636/15 www.nature.com/hr

ORIGINAL ARTICLE

Non-dipping patterns and parameters in patients with Behcet’sdisease

Gulperi Celik1, Sema Yilmaz2 and Serpil Ergulu Esmen2

Behcet’s disease is a multisystemic involving and of various sizes. Non-dipping status, augmentation index and pulse wave velocity are important determinants of cardiovascular mortality and morbidity. We investigated the non- dipping status and arterial stiffness in patients with Behcet’s disease. In this cross-sectional study, we examined the vascular parameters of 96 patients with Behcet’s disease (53% female) and 60 age- and sex-matched control subjects. The non-dipping status and arterial distensibility were assessed using a Mobil-O-Graph Arteriograph, an automatic oscillometric device. In total, 65.6% of 96 patients were systolic non-dippers, and 34.4% exhibited high augmentation indices. Ten percent of the control subjects were systolic non-dippers, and 11.7% exhibited high augmentation indices. Nocturnal decreases in systolic blood pressure correlated with central systolic blood pressure and diastolic blood pressure, as well as nocturnal decreases in diastolic blood pressure. Furthermore, non-dipper patients with Behcet’s disease exhibited higher nocturnal cardiac outputs than did dipper patients with Behcet’s disease. Augmentation index correlated negatively with C-reactive protein and correlated positively with both 24 h and nocturnal peripheral resistance, as well as 24 h pulse wave velocity. The patients with high augmentation indices exhibited lower creatinine clearance, as well as lower nocturnal cardiac outputs, higher 24 h peripheral resistance and higher 24 h pulse wave velocities. Non-dipping status and arterial stiffness may exacerbate the harmful cardiovascular effects of the other. In addition to conventional risk factors, non-dipping status and arterial stiffness should be examined during the follow-up evaluations of patients with Behcet’s disease. Hypertension Research (2015) 38, 856–861; doi:10.1038/hr.2015.86; published online 13 August 2015

Keywords: augmentation index; Behcet’s disease; cardiac output; non-dipping status; pulse wave velocity

INTRODUCTION this so-called sleep-time dipper pattern exhibit an abrupt rise in the Behcet’s disease (BD) was first described in 1937 by Hulusi Behcet and morning, just before the commencement of diurnal activity, peaking is an autoinflammatory disease and multisystemic vasculitis of an during the morning or afternoon hours. Thereafter, these pressures unknown origin characterized by mucocutaneous, ocular, arthritic and gradually decline, reaching their lowest levels during night-time sleep. vascular manifestations.1–3 As the primary pathological feature of BD This BP circadian pattern is characterized by night-time SBP and DBP is vasculitis, it is often exacerbated by vascular complications, with an mean levels 10–20% lower than those observed during the daytime. In incidence of vascular involvement ranging from 7 to 29%.4 Large- normotensive and hypertensive individuals, the failure of night-time vessel vasculitis occurs in a subgroup of patients with BD at high risk BP to decline 410% compared with daytime BP (non-dipping status) for disease-related morbidity and mortality.5 Recognition of patients at is associated with increased target organ damage. The circadian risk, as well as the early detection of vasculitis and aggressive rhythm of BP also affects .11–13 treatment, is essential for providing optimal care for these Several authors have demonstrated that arterial stiffness is increased patients.5,6 in BD.14–17 Ample data exist demonstrating that increased systemic Twenty-four hour ambulatory blood pressure (BP) monitoring has inflammation has a deleterious effect on both the structure and the been used to demonstrate the diurnal rhythm of arterial BP.7 After function of the arterial wall and may enhance the atherosclerotic many decades of investigation, it has been established that target organ process.14,16,18 Both acute and chronic inflammation have been damage is more closely associated with ambulatory BP monitoring linked with increased arterial stiffness and altered pressure wave than with clinical BP, and specific features of the 24 h BP pattern have reflections.14–17 been linked to the progressive injury of target tissues and the triggering Arterial stiffness is a reliable predictor of subsequent cardiovascular of both cardiac and cerebrovascular events.8–10 Among normotensive mortality and vascular damage.19 Augmentation index (AIx) and pulse individuals, both the systolic BP (SBP) and the diastolic BP (DBP) of wave velocity (PWV) are ideal indicators of arterial stiffness.2,15,17,20,21

1Division of Nephrology, Department Of Internal , Faculty of Medicine, Selcuk University, Konya, Turkey and 2Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Selcuk University, Konya, Turkey Correspondence: Dr G Celik, Division of Nephrology, Department of Internal Medicine, School of Medicine, Selcuk University, Konya 42075, Turkey. E-mail: [email protected] Received 14 January 2015; revised 2 June 2015; accepted 8 June 2015; published online 13 August 2015 Non-dipping blood pressure patterns in Behcet’s disease GCeliket al 857

In other words, PWV and AIx have been used to evaluate the Hemodynamic parameters and the estimation of pressure wave viscoelastic properties of the large arteries.2,22 Increased and premature reflections pressure reflections emerge that are superimposed over the generic For each patient, BP was measured three times in the sitting position using a pulse wave ejected by the heart. Their accumulation results in an mercury sphygmomanometer, using the first and fifth Korotkoff sounds to elevation of aortic SBP known as augmentation. The percent ratio of identify the systolic and diastolic values, respectively. this augmentation to the aortic is called AIx, which Ambulatory BP and arterial distensibility were assessed over 24 h (24 h) using a Mobil-O-Graph Arteriograph (I.E.M. GmbH, Stolberg, Germany), an represents a percentage of the central pulse pressure. The AIx is often − 1 23 oscillometric device that yields a simultaneous measurement of brachial BP, normalized against a heart rate of 75 beats min . PWV and AIx. The device is supported with an expert software package, There are few data regarding the indicators of arterial stiffness, non- hypertension management system, for the analysis of all registered measure- dipping patterns and related parameters in these patients. In a cohort ments. Additionally, the device is capable of measuring central BP and AIx of 96 consecutive patients with BD, we assessed dipping patterns in an using an integrated pulse wave analysis device. Using the Austrian Research attempt to interpret the different pathophysiological mechanisms Centers Solver method (Austrian Institute of Technology, Vienna, Austria), underlying the potential alterations in both central and peripheral waveforms were recorded with a regular oscillatory brachial cuff suitable for hemodynamics. We also examined the parameters related to the ambulatory measurement. The Austrian Research Centers Solver method is a magnitudeofwavereflection pressure and local large stiffness. novel approach for determining aortic SBP and AIx based on oscillometric BP measurements using a common cuff. The method uses the pulse waves assessed We hypothesized that patients with BD exhibit high rates of non- 25,26 dipper BP patterns; however, these patients may also experience at the brachial artery. The device was applied in the morning, and the patients were allowed to return home with the instruction to attend to their central and peripheral hemodynamic disturbances that adversely affect usual activities and return to the hospital the following day for device removal. arterial stiffness parameters. Automated results were provided by the device’s internal calculations. These results included 24 h, day and night (1) peripheral and central aortic systolic, MATERIALS AND METHODS diastolic and mean BP and pulse pressures; (2) cardiac output (CO); (3) Subjects peripheral resistance (PR) (4) nocturnal decreases in systolic BP (NDSBP) and This study included 96 patients with BD who fulfilled the International Study nocturnal decreases in diastolic BP; patients without a nocturnal SBP decline Group criteria24 and control subjects. For the control group, 60 healthy age- ⩾ 10% compared with daytime values were referred to as non-dippers;7 (5) and sex-matched subjects were recruited from our hospital staff and from aortic augmentation pressure, AIx and AIx standardized against a heart rate of among healthy volunteers. The study was approved by the Hospital Ethics 75 beats per minute (AIx@75); and (6) PWV. Because the accepted cut-off Committee, and informed, written consent was provided by each patient. value for AIx with respect to cardiovascular mortality is 25%, we used 25% as Patients were included if they met the following criteria: 418 years of age; an our cut-off value.27 office BP o140/90 mm Hg; and a 24 h BP o125/80 mm Hg. We took great care to exclude patients with known cardiovascular disease or risk factors for Statistical analysis cardiovascular disease. The exclusion criteria included a major cardiovascular Variables are presented either as the mean ± s.d. or as frequencies. The data had disease, including previous myocardial infarction, congestive , previously been submitted for a normality test (Kolmogorov–Smirnov). In valvular heart disease, atrial fibrillation, arterial hypertension, insulin-dependent addition to the descriptive statistics (mean ± s.d. and frequencies), Student’s diabetes mellitus, non-insulin-dependent diabetes mellitus, dyslipidemia, exces- t-test was used for normally distributed variables, and the Mann–Whitney sive alcohol consumption and the use of antihypertensive medications and U-test was used for variables that were not normally distributed. For the additional cardiovascular or metabolic drugs, including statins, hormone comparison of qualitative data, either the chi-square test or Fisher’s exact test replacement therapy, nitrates, angiotensin-converting enzyme inhibitors, angio- was used. The correlations among the data were analyzed using Pearson’s tensin receptor blockers and diuretics. Smoking habits were also taken into correlation test. We undertook a linear regression analysis to evaluate the account. The duration of the disease in the BD group was calculated as the time relative significance of the parameters. All tests were two-tailed, and the level of at which the International Study Group criteria were fulfilled until the time of significance was set at Po0.05. The data were analyzed using the SPSS statistical examination. package program, version 15, for Windows (SPSS, Chicago, IL, USA). For each patient, the clinical data included age, sex, cutaneous (genital and oral) ulcers and eye, central nervous system, arterial, venous and joint RESULTS – involvement. Medical treatment included colchicine, corticosteroids (0.5 1 Ninety-six patients were enrolled; the majority were female (53%), mg kg − 1 per day), immunosuppressants (cyclophosphamide or azathioprine), with a mean age of 37.98 ± 11.67 years; the mean disease duration was oral anticoagulation and low-dose aspirin. Each patient was evaluated during ± both active and inactive disease periods. At the time of examination, the 73.75 88.65 months; 65.6% were systolic non-dippers; and 34.4% presence of two or more of the following clinical features denoted active exhibited high AIx@75 values. Six (10%) of the control subjects were disease: oral ulceration; genital ulceration; skin lesions; ocular lesions; systolic non-dippers, and 7 (11.7%) exhibited high AIx@75. The active major vessel disease; and active major organ involvement, including number of patients with BD with inactive disease was 53, whereas 43 active gastrointestinal or neurological lesions. Subjects with either one lesion or patients suffered from active disease. Table 1 summarizes the clinical no lesions had inactive disease. features, biochemical parameters, BPs and central hemodynamics of the patients with BD and the control subjects. Biochemical data Nocturnal SBP decreases correlated with disease duration, albumin, A venous blood sample was obtained from each patient following overnight 24-h urinary albumin, central SBP and DBP, 24-h PWV, Night fasting. Serum creatinine, urea, glucose, total , triglyceride, high- AIx@75 and nocturnal PWV. AIx@75 correlated negatively with height density lipoprotein cholesterol, low-density lipoprotein cholesterol, albumin, and CRP and correlated positively with 24 h and nocturnal PR, as well total protein, calcium, phosphorus, C-reactive protein (CRP), 24 h (h) urinary as 24 h and nocturnal PWV (Table 2). When we performed the uric acid, 24 h urinary albumin and 24 h urine protein were measured using an ARCHITECT C16000 (Abbott Diagnostics, Illinois, IL, USA). The erythrocyte multivariate linear regression analysis, NDSBP correlated with 24-h β = − P = β = − Po sedimentation rate (ESR) was determined using a TEST-1 analyzer SBP ( 0.546, 0.048), 24- h PWV ( 3.799, 0.001), (Alifax, Padova, Italy). Complete blood count measurements, including nocturnal PWV (β = − 3.939, Po0.001), nocturnal AIx@75 hemoglobin, hematocrit and lymphocytes, were performed using a Sysmex (β = − 0.152, P = 0.017). 24- h PWV, nocturnal PWV and nocturnal XT 2000 (Roche, Basel, Switzerland). AIx@75, all of which were significant independent predictors of

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Table 1 Sociodemographic characteristics, biochemical parameters, Table 2 Correlation coefficients of nocturnal systolic blood pressure blood pressures and central hemodynamics in BD patients and decrease and augmentation index value, standardized to a heart rate controls of 75 beats per minute (AIx@75)

Parameters BD patients Controls P-values Nocturnal SBP decrease 24-h AIx@75 Age (years) 37.98 ± 11.67 35.23 ± 12.58 0.167 Female/male n (%) 53(60)/44(40) 34(57)/26(43) 0.318 rvalues P-values r values P-values Mean disease duration (months) 73.75 ± 88.65 —— Weight (kg) 69.86 ± 12.06 67.31 ± 11.26 0.219 Duration of Disease (month) − 0.212 *0.040 0.140 0.195 Height (cm) 1.66 ± 0.08 1.64 ± 0.14 0.976 Height (cm) 0.156 0.167 − 0.360 *0.009 −2 BMI (kg m )26.56± 4.86 24.51 ± 5.78 0.176 − Albumin (mg dl 1) 0.363 *0.003 0.018 0.507 Glucose (mg dl − 1)94.20± 20.04 92.43 ± 7.96 0.698 CRP (mg l − 1) − 0.058 0.713 − 0.381 *0.004 Total cholesterol (mg dl − 1)181.67± 43.22 174.79 ± 30.84 0.384 24-h urinary albumin − 0.266 *0.009 − 0.013 0.914 LDL-cholesterol (mg dl − 1)114.16± 34.31 121.55 ± 35.22 0.310 24-h central SBP (mm Hg) − 0.384 *0.003 − 0.232 0.068 HDL-cholesterol (mg dl − 1)44.97± 10.48 42.57 ± 10.45 0.234 24-h central DBP (mm Hg) − 0.321 *0.016 − 0.178 0.196 − 1 Triglycerides (mg dl )126.46± 76.00 131.81 ± 43.56 0.685 − 24-h PR (s-mm Hg ml 1) − 0.266 0.012 0.430 *0.001 24-h SBP 113.92 ± 12.57 112.31 ± 10.34 0.430 − 24-h PWV (m s 1) − 0.187 *0.026 0.409 *0.002 24-h DBP 73.17 ± 10.09 71.27 ± 8.43 0.256 NDDBP 0.736 *o0.001 − 0.40 0.801 24-h MBP 92.44 ± 14.73 90.15 ± 8.83 0.303 Nocturnal central SBP (mm Hg) − 0.660 *o0.001 0.250 0.612 24-h pulse pressure 40.62 ± 6.20 41.09 ± 6.61 0.666 Nocturnal central DBP (mm Hg) − 0.604 *o0.001 0.180 0.206 24-h heart rate 75.88 ± 9.04 73.00 ± 10.82 0.089 Nocturnal CO (l min − 1) − 0.457 *o0.001 − 0.161 0.237 24-h AIx@75 22.66 ± 7.94 21.18 ± 7.45 0.265 − Nocturnal PR (s-mmHg ml 1) − 0.338 0.001 0.471 *o0.001 Systolic non-dipper n (%) 63(65.6) 6 (10) *o0.001 Nocturnal AIx@75 − 0.254 *0.017 0.827 *o0.001 The night reduction in SBP 7.02 ± 6.79 10.77 ± 3.30 *o0.001 − Nocturnal PWV (m s 1) − 0.300 *0.024 0.427 *o0.001 Nocturnal SBP 108.04 ± 15.45 103.33 ± 10.29 *0.031 Nocturnal DBP 67.10 ± 11.96 63.57 ± 7.90 *0.040 Abbreviations: 24-h, 24-hour; CO, cardiac output; CRP, C-reactive protein; DBP, diastolic blood pressure; NDDBP, nocturnal decrease in the diastolic blood pressure; PR, peripheral resistance; Nocturnal MBP 85.91 ± 13.10 81.87 ± 8.05 *0.032 s, second; SBP, systolic blood pressure. o Nocturnal pulse pressure 40.94 ± 7.33 39.83 ± 7.53 0.286 *P 0.05. Nocturnal heart rate 67.48 ± 9.88 66.07 ± 10.00 0.395 Nocturnal AIx@75 21.34 ± 10.62 19.71 ± 11.37 0.318 Furthermore, despite the inability to achieve statistical significance, the Abbreviations: 24-h, 24-hour; Alx@75, augmentation index value, standardized to a heart rate of 75 beats per minute; BD, Behcet’s disease; BMI, body mass index; DBP, diastolic blood patients with active BD included a higher percentage of patients with pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MAP, mean arterial low AIx@75 values (18/58% vs. 13/41.9%; P = 0.6). pressure; SBP, systolic blood pressure. Values are expressed as mean ± s.d. *Po0.05. DISCUSSION BD is a chronic relapsing inflammatory process; its predominant decreases in nocturnal BP. In the multivariate model, 24 h AIx@75 histopathology is vasculitis. The vasculitis of BD is distinctive because correlated with height (β = − 0.338, P = 0.040), CRP (β = − 0.380, of the involvement of both veins and arteries of all sizes, although P = 0.004) and nocturnal PR (β = 0.556, P = 0.036). The linear different histological features may be present at different sites. The regression analysis demonstrated that both height and CRP correlated inflammatory changes in the large arteries are typical of vasculitis, but negatively with increased AIx@75. the lack of granulomatous inflammation and the tendency for The relationships between nocturnal decreases in SBP and the formation are also distinctive.5,6,28,29 This inflammation clinical, demographic and laboratory parameters of the patients with may contribute to either the initiation or the progression of arterial BD were analyzed using Χ2- and t-tests where indicated. Among the stiffness. In this study, we evaluated NDSBP, as well as AIx@75, an patients with non-dipper BD, the AIx values were elevated compared arterial stiffness parameter, and several additional parameters in with the dipper patients with BD. Furthermore, the non-dipper patients with BD. In this study, 65.6% of the patients were systolic patients with BD exhibited higher night COs than the dipper patients non-dippers, whereas 10% of the control subjects were systolic non- with BD (Figure 1). The central hemodynamics, BP patterns and dippers. NDSBP correlated with 24 h PWV, nocturnal CO, nocturnal arterial stiffness parameters of the non-dipper and dipper patients with AIx@75 and nocturnal PWV. AIx@75 correlated with height, CRP and BD are included in Table 3. PWV. The patients with high AIx@75 values exhibited higher 24 h PR When we divided the patients into two groups according to AIx@75 and PWVs, as well as lower nocturnal COs. values (the AIx@75o25% patient group: patients with BD with low In the present study, 65.6% of the patients were systolic non- AIX vs. AIx@75425% patient group: patients with BD with high dippers, whereas 10% of control subjects were systolic non-dippers. AIX), the patients with high AIx@75 values were mostly female The incidence of non-dipping BP patterns among the patients with (71.0%) and were shorter (1.63 ± 0.08 vs.1.68± 0.08; P = 0.013). BD patients was similar, and even higher than the incidence of non- These patients also exhibited lower high-density lipoprotein dipping patterns among the patients with hypertension. Indeed, (41.95 ± 9.76 vs.47.93± 9.37; P = 0.031) and creatinine clearance abnormal decreases in nocturnal BP were observed in 30–50% of (125.32 ± 21.34 vs.144.77± 39.16; P = 0.036) values and higher 24 h the patients with hypertension.12 The non-dippers exhibited higher PR (1.35 ± 0.15 vs.1.21± 0.10; Po0.001), 24 h PWV (5.98 ± 1.17 vs. supine brachial and central SBPs, significantly different central 5.34 ± 0.70; P = 0.021) and nocturnal PR (1.38 ± 0.18 vs.1.15± 0.14); hemodynamics, and elevated left ventricular mass indices compared Po0.001) and PWV (5.91 ± 1.26 vs.5.20± 0.60; P = 0.013) values with the dippers. These cardiovascular anomalies may contribute to an than their counterparts in the other group (Figures 2 and 3). increased risk of cardiovascular mortaility and all-cause mortality.

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Table 3 The central hemodynamics, BP patterns and arterial stiffness parameters of non-dipper and Dipper BD patients

Non-dipper Patients Dipper Patients P value

24-h SBP (mm Hg) 115.67 ± 13.01 109.69 ± 10.48 0.041 24-h DBP (mm Hg) 74.71 ± 10.31 69.42 ± 8.63 0.024 24-h central SBP (mm Hg) 108.27 ± 12.45 100.88 ± 10.08 0.009 24-h central DBP (mm Hg) 76.41 ± 10.56 70.42 ± 8.08 0.011 24-h Alx@75 (%) 22.13 ± 7.60 18.49 ± 6.42 0.044 24-h CO (l min − 1)4.12± 0.42 3.88 ± 0.37 0.018 DMSBP (mm Hg) 94.73 ± 12.60 88.19 ± 9.09 0.019 DMDBP (mm Hg) 56.67 ± 12.19 49.88 ± 11.11 0.016 Nocturnal decrease in 8.29 ± 10.19 20.17 ± 8.01 o0.001 DBP (mm Hg) Nocturnal SBP (mm Hg) 112.57 ± 14.88 97.08 ± 10.69 o0.001 Nocturnal DBP (mm Hg) 70.57 ± 11.16 58.69 ± 9.53 o0.001 Nocturnal MAP (mm Hg) 89.76 ± 12.42 76.58 ± 9.70 o0.001 Nocturnal PP (mm Hg) 41.98 ± 7.91 38.42 ± 4.96 0.036 Nocturnal central SBP (mm Hg) 106.60 ± 14.56 92.19 ± 11.06 o0.001 Nocturnal central DBP (mm Hg) 71.65 ± 11.62 59.85 ± 9.59 o0.001 Nocturnal CO (l min − 1)3.98± 0.63 3.45 ± 0.60 0.003 Nocturnal Alx@75 (%) 20.63 ± 11.93 17.54 ± 9. 80 0.045 Nocturnal maximum 129.57 ± 21.12 115.81 ± 16.57 0.004 Figure 1 Cardiac output (CO) of dipper and non-dipper patients with Behcet’s Disease (BD). Non-dipper BD patients had higher night CO than SBP (mm Hg) dipper BD patients. Nocturnal maximum 84.14 ± 12.83 74.54 ± 12.83 0.002 DBP (mm Hg) NMSBP (mm Hg) 97.98 ± 14.44 81.65 ± 10.70 o0.001 NMDBP (mm Hg) 57.16 ± 12.05 45.19 ± 8.55 o0.001 Many studies have demonstrated that non-dippers suffer more ESLV (%) 16.81 ± 26.07 5.38 ± 9.26 0.033 pronounced target organ injury, particularly to the heart, brain and EDLV (%) 21.65 ± 26.95 7.88 ± 12.88 0.015 kidney, compared with dippers.11,30 In our study, nocturnal SBP Abbreviations: 24-h, 24-hour; Alx@75, augmentation index value, standardized to a heart rate of decreases correlated with central SBP and DBP, as well as nocturnal 75 beats per minute; BD, Behcet’s disease; BP, blood pressure; CO, cardiac output; DBP, decreases in diastolic BP. Additionally, NDSBP correlated negatively diastolic blood pressure; DMDBP, diurnal minimum DBP; DMSBP, diurnal minimum SBP; EDLV, exceeding the diastolic limit value; ESLV, exceeding the systolic limit value; MAP, mean with 24-h and nocturnal PWV. The abnormal diurnal central arterial pressure; NMDBP, nocturnal minimum DBP; NMSBP; nocturnal minimum SBP; PP, fi pulse pressure; SBP, systolic blood pressure. hemodynamic patterns were signi cant in the patients with BD. The Values are expressed as mean ± s.d. non-dipper patients with BD exhibited higher 24-h central SBPs, 24-h central DBPs, 24-h Alx@75, diurnal minimum SBPs, diurnal mini- mum DBPs, nocturnal MAPs, pulse pressures, central SBPs, central DBPs, maximum SBPs and maximum DBPs. The deleterious effects of systemic inflammation on the aforementioned surrogate markers of become an important issue with respect to BD,16,31 which is associated cardiovascular risk may have resulted in increased central BP in the with increased arterial stiffness and involves pressure wave reflections absence of increased peripheral BP and represent a pathophysiological higher than those of control groups.14,15,32–34 The gradual increases of link between inflammation and increased cardiovascular risk.14–17 arterial stiffness, as well as the decrease in diameter from the central to Furthermore, the non-dipper pateints with BD exhibted higher night the peripheral arteries, leads to the generation of pressure wave COs than the dipper patients with BD. Our findings were consistent reflections.32–34 with those of Takakuwa et al.7 and Colleman et al.11 who reported that In current study, AIx@75 was negatively correlated with CRP. In nocturnal cardiac output and volume were significantly higher addition, in despite not reach statistical significance, group of patients among non-dippers. The supine brachial SBP abnormality was with active BD included higher percentage of patients with low accompanied by a significantly higher central SBP in the supine AIx@75 values. The increased arterial stiffness may be attributed to position. When the non-dippers moved into the supine position, both either acute or chronic inflammatory processes associated with BD.17 the brachial and the central SBP increased, whereas the mean arterial It appears that even relapsing inflammatory episodes may have pressure failed to change despite a drop in heart rate. These chronically stable detrimental effects on both the large and the small hemodynamic alterations were initiated by the posture-induced arteries due to structural changes (for example, arterial remodeling) at stimulation of cardiopulmonary low-pressure and arterial (carotid the levels of both macro- and the microcirculation.14,16 On the other and aortic) high-pressure sensors when the non-dippers moved into hand, during the acute phase of the inflammatory process, particular the supine position.11 patterns of central BPs may develop due to functional changes In this study, 34.4% of the patients exhibited high AIx@75 values, (peripheral vasodilation), leading to alterations in pressure wave whereas, 11.7% of the control subjects exhibited high AIx@75. The reflections. These deleterious effects of systemic inflammation on the percentage of patients with BD with high AIx@75 values was higher aforementioned surrogate markers of cardiovascular risk may lead to than that of the control group. The detrimental effects of systemic increased central BPs in the absence of increased peripheral BP and inflammation on arterial stiffness are well established. Both the represent a pathophysiological link between inflammation and structural and the functional features of the vascular system have increased cardiovascular risk.14,15 Indeed, Vlachopoulos et al.35

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In the present study, AIx@75 correlated negatively with height and correlated positively with 24 h and nocturnal PR, as well as 24 h and nocturnal PWV. The patients with high AIx@75 were shorter; the percentage of female patients was higher in the high AIx@75 group. Additionally, the patients with high AIx@75 also exhibited lower nocturnal COs and higher PR and PWV values than the patients with BD patients with low AIx@75. AIx quantifies pressure wave reflections; however, it is dependent not only on the amplitude of the reflected pressure wave but also on the timing of the arrival of the reflected wave within the cardiac cycle. Therefore, AIx also depends on height, sex (due to differences in height), heart rate/ejection duration and PWV.36 Although increased arterial stiffness, and hence increased PWV, tends to cause the earlier arrival of the pressure wave, resulting in higher Aix; this effect may be counterbalanced by peripheral vasodilation, tachycardia, or other modulators of the timing of the arrival of the reflected pressure wave under specific conditions.14 In conclusion, the present study demonstrated that patients with BD exhibit significantly increased arterial stiffness compared with healthy control subjects. These findings have spawned the hypothesis that the inflammatory processes associated with BD may cause endothelial dysfunction. Elevations in the markers of endothelial Figure 2 Peripheral resistance (PR) of Behcet’s Disease patients with low dysfunction (thombomodulin and adhesion molecules) and low- fl fl and high AIx@75. Patients with high AIx@75 had higher 24 h PR and grade in ammation (proin ammatory cytokines, C-reactive protein nocturnal PR than those of the other group. AIx@75, augmentation index and serum amyloid A) are indicative of their roles in the pathophy- value, standardized to a heart rate of 75 beats per minute. siology of most of the immune-mediated cardiovascular events associated with BD.37 However, non-dipper systolic hypertension is associated with increased cardiovascular morbidity and mortality.38 Patients with systolic non-dipper hypertension were more common in the BD group than in the control group. There may be a relationship between systolic non-dipper hypertension and BD. Systolic non-dipper status in the setting of BD may result in subsequent vascular damage within a 24-h period associated with endothelial hyperactivity, which may cause . A recent study investigating the relation- ship between isolated systolic increases in BP (non-dippers) and the incidence of hypertension among elderly patients observed that aortic occurred only among non-dippers.39 More recently, another study demonstrated that non-dipper patients with hyperten- sion exhibited a higher thoracic aortic diameter compared with dipper patients.40 This finding is unusual, as the effect of systolic non-dipper hypertension itself is not believed to be significant among patients with BD; it may associated with the development of aneurysms and non- atherosclerotic coronary artery disease.

Study limitations The limitations of our study included the small size of our study population and its high percentage of female patients with BD.

CONCLUSION Arterial stiffness and non-dipping status may exacerbate the harmful Figure 3 Pulse wave velocity (PWV) of Behcet’s Disease patients with low cardiovascular effects of the other. In addition to conventional risk and high AIx@75. Patients with high AIx@75 had higher 24 h PWV and factors, arterial stiffness and non-dipping status should not be nocturnal PWV than those of the other group. AIx@75, augmentation index overlooked during the follow-up evaluations of patients with BD. value, standardized to a heart rate of 75 beats per minute; PWV, Pulse Wave Longitudinal studies in a large population are warranted in order to Velocity. determine the prognostic implications of increased stiffness para- meters in the setting BD. Additionally, future studies with large sample sizes are necessary to elucidate the underlying hemodynamic recently demonstrated that although PWV may increase abruptly mechanisms of blunted nocturnal reductions in the BPs of patients in the presence of acute inflammation, AIx may decrease. The with non-dipper BD. low-pressure wave reflection indices were attributed to peripheral vasodilation induced by transient acute systemic inflammation, CONFLICT OF INTEREST resulting in an attenuation of the reflected pressure wave. The authors declare no conflict of interest.

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